Coronary Heart Disease is the leading cause of death in our society. Underlying this disease is the pathologic process known as atherosclerosis. The central theme of this Program is to define aspects of lipoprotein metabolism important in atherogenesis. Atherosclerosis occurs when plasma low density lipoproteins (LDL) get deposited in the artery wall. Atherosclerotic lesions rich in cholesteryl esters develop in response to LDL deposition. Studies in this program project will help define how LDL precursor lipoproteins are actually made inside cells (Project by Shelness), how concentrations are controlled, and properties of LDL that make them more atherogenic. We have identified an enzyme in the liver and intestine, termed ACAT2, that appears to be important in this context, and we will use genetically engineered mice that no longer have this enzyme to show protection against atherosclerosis (Project by Rudel). We will test the hypothesis that cholesteryl oleate accumulation in plasma as LDL promotes atherosclerosis. high density lipoproteins (HDL) are the class of lipoproteins that help remove cholesterol from arteries. We will do studies to help determine how HDL particles are made. We know that the principal protein of HDL, called apoA-I, is secreted without lipid into plasma and then assembles lipid after interaction on the surface of cells with a transporter termed ABCA1. The characteristics of this interaction will be measured (Project by Parks). Further, the properties of apoA-I that determine efficient function of this apolipoprotein in lipid assimilation and transport will be assessed in Project by Sorci-Thomas. In both of these projects, genetically engineered mice will provide specific insights into molecular physiology. Finally, in Project 5, we will study the main breakdown product of cholesterol in the body, bile acids. We will examine the efficiency with which these molecules undergo enterohepatic recirculation and how this may affect plasma lipoprotein concentrations and atherosclerosis. A mouse model has been created that lacks the intestinal bile acid transporter protein that recovers the bile acids from the intestine, and this mouse will be studied to help define specific aspects of the regulation of this metabolic axis. Overall, this program project will provide basic information that will help us understand the role of lipoprotein metabolism in atherosclerosis so that prevention of CHD can be more readily achieved.